Abstract
The aim of this study was to evaluate the clinical and pathologic features of a rare tumor (adenoma malignum, AM). We retrospectively analyzed the medical records of 18 patients diagnosed with AM at a single institute between March 1992 and November 2009. The median age of the patients was 45.8 years (range 29–76 years) and the mean follow‐up period was 49.2 months (range 4–168 months). A preoperative cytologic diagnosis (Papanicolaou smear) of AM was made in 22.2% (4/18) of the cases. Ten (55.6%) of the 18 patients were misdiagnosed with other benign diseases and underwent hysterectomies, which confirmed AM. Sixteen patients with AM were in the early stage (IB1, 11/18; IB2, 5/18) and the other two patients were in the advanced stage. Fourteen of 18 patients (77.8%) had pure AM alone. Adjuvant therapy was administered to eight of the patients (44.4%) with AM. The recurrence rate was zero, but the disease progressed in two of the patients (11.1%), who died of the disease. The 5‐year survival rate was 88.8%. A cytological diagnosis of AM based on a Papanicolaou smear is rarely made; a deep biopsy (cone biopsy or endocervical curettage) is necessary to diagnose this rare tumor preoperatively when there is any clinical suspicion of AM.
Keywords: Adenoma malignum, Clinicopathologic, Rare tumor
Introduction
Adenoma malignum (AM) is a rare variant of adenocarcinoma of the uterine cervix. AM comprises 1–3% of all cervical adenocarcinomas [1]. Unlike typical cervical carcinoma, most cases of AM exhibit an endophytic rather than an exophytic growth pattern. Another characteristic of AM is that it mimics multiple nabothian cysts as a benign‐appearing tumor. In addition, the screening method for normal uterine cervical cancer has occasionally been used to diagnose AM. These findings make preoperative diagnosis of AM difficult and can result in surgery being performed based on misdiagnosis. The final diagnosis of AM is often determined from surgical specimens.
AM of the uterine cervix is so rare that the real nature and clinical course have not been fully clarified. In addition, standard treatment, including surgery and adjuvant therapy, is not well documented.
In the present study, all of the patients underwent surgery and follow up in a single institute. The current paper focuses on the clinicopathologic aspects of AM, a very rare type of cervical cancer.
Materials and methods
Eighteen patients diagnosed with AM of the uterine cervix between March 1992 and November 2009 were identified from the medical records of Cheil General Hospital and Women's Healthcare Center. The medical records were analyzed for information on demographic characteristics, surgical findings, and clinical outcomes.
The pathologic classification of cervical adenocarcinoma was carried out according to the 1994 WHO classification [2]. The histopathologic definition and characteristic features of AM are as follows: (1) a highly differentiated mucinous adenocarcinoma in which most of the glands are impossible to distinguish histologically from normal endocervical glands; (2) cytologically bland glands that vary in size and shape; (3) increased mitotic activity; (4) hyperplastic appearance of the glands at the surface; and (5) an increased number of glands positioned deeper than the lower level of the normal endocervical glands.
The criteria of the International Federation for Obstetrics and Gynecology (FIGO) were applied to stage the tumors. The histologic grading was based on the architectural features of the tumors, classified as follows: grade 1, well‐differentiated tumor; grade 2, moderately differentiated tumor; and grade 3, poorly differentiated tumor.
Surgery was the first treatment with or without adjuvant therapy for all patients. The adjuvant therapy protocol used was divided into three types, concurrent chemoradiotherapy (CCRT), radiotherapy alone, or chemotherapy alone.
Kaplan‐Meier curves were used to calculate the mean overall survival (OS). The Statistical Package for Social Science (SPSS, Inc., Chicago, IL, USA) was used for statistical analysis. A p value <0.05 was considered significant.
Results
The mean age of the entire population was 45.8 years (range 29–76 years). The major symptoms at the time of diagnosis were profuse vaginal discharge (8/18, 44.4%) and vaginal bleeding (6/18, 33.3%). Cytologic screening of the uterine cervix revealed negative cytology results in 14 cases (77.7%) and abnormal findings in four cases (22.2%). Two of the four cases with abnormal cytology were shown to be adenocarcinoma. Further evaluation tools included cone biopsy and dilatation and curettage (D&C) of the uterine endometrium. The total preoperative diagnosis rate was 44.4% (8/18). There were two cases of AM combined with Peutz–Jeghers syndrome. Table 1 lists demographic data for the 18 patients.
Table 1.
Preoperative clinicopathological characteristics.
| Mean age (y) | 45.8 (range 29–76) |
| Most common symptom | |
| Profuse vaginal discharge | 8/18 (44.4%) |
| Vaginal bleeding | 6/18 (33.3%) |
| Other | 4/18 (22.2%) |
| Cytology | |
| Negative | 14/18 (77.7%) |
| Abnormal findings | 4/18 (22.2%) |
| Adenocarcinoma | 2 |
| Atypical squamous cells, cannot rule out a high‐grade lesion | 1 |
| Low‐grade squamous intraepithelial lesions | 1 |
| Biopsy tools | |
| Cone | 5/18 (27.8%) |
| Dilatation and curettage | 4/18 (22.2%) |
| Peutz–Jeghers syndrome | |
| Yes | 2/18 (11.1%) |
| No | 16/18 (88.9%) |
| Preoperative diagnosis | |
| Yes | 8/18 (44.4%) |
| No | 10/18 (55.6%) |
The mean tumor diameter was 3.61 cm (range 1.0–7.5 cm). Sixteen cases were classified as stage IB and two cases were classified as advanced stage according to the 1985 FIGO staging system. A type III radical hysterectomy with pelvic lymph node dissection (PLND) was performed in eight cases (44.4%) and 10 patients underwent a type I hysterectomy with or without PLND (5 with PLND and 5 without PLND). Among the 13 cases with PLND, lymph node metastasis was detected in three cases, two of which were advanced. One case with a stage IB1 tumor had co‐occurrence of moderately differentiated mucinous adenocarcinoma. Fourteen cases (77.8%) had AM alone and four cases (22.2%) had AM combined with other types of adenocarcinoma. Lymph‐vascular space invasion (LVSI) was positive in five cases; four cases had positive LVSI with other adenocarcinoma (Table 2).
Table 2.
Treatment and pathology of adenoma malignum (n = 18).
| Stage | |
| IB1 | 11/18 (61.1%) |
| IB2 | 5/18 (27.8%) |
| III | 1/18 (5.6%) |
| IV | 1/18 (5.6%) |
| Mean tumor diameter (cm) | 3.61 (range 1.0–7.5) |
| Operation type | |
| Type I hysterectomy | 5/18 (27.8%) |
| Type I hysterectomy with PLND | 5/18 (27.8%) |
| Type III hysterectomy with PLND | 8/18 (44.4%) |
| Co‐occurrence of other adenocarcinoma | |
| Adenoma malignum alone | 14/18 (77.8%) |
| Mixed type | 4/18 (22.2%) |
| Adjuvant therapy | |
| Yes | 8/18 (44.4%) |
| No | 10/18 (55.6%) |
PLND = pelvic lymph node dissection.
Eight patients underwent adjuvant therapy after the initial surgical treatment. Four, three, and one cases underwent CCRT, radiotherapy alone, and chemotherapy alone, respectively. Two advanced cases with treatment failure died of the disease. In the first case (stage IV with positive metastasis to the para‐aortic lymph nodes), the patient received CCRT with paclitaxel and carboplatin. The patient declined further treatment and her follow‐up was lost for 8 months. On follow‐up evaluation, the patient had multiple peritoneal metastases and bilateral hydronephrosis; thus, she was not eligible for salvage treatment. In the second case (stage IIIA), the patient underwent neoadjuvant CCRT with paclitaxel and carboplatin. A follow‐up imaging study showed progression of the disease. A type I hysterectomy with unilateral salpingo‐oophorectomy was performed and the debulking rate was suboptimal owing to a radiation‐induced frozen pelvis and multiple cancer invasion. The patient died of disease progression on the 18th post‐operative day.
The other 16 patients survived without recurrence. The mean follow‐up period was 49.2 months (range 4–168 months).
Discussion
AM of the uterine cervix was first described by Gusserow in 1870 [3]. In 1963, McKelvey and Goodlin reported five AM cases [4]. In 1975, the term minimal deviation adenocarcinoma was proposed by Silverberg and Hurt [5] for tumors with good differentiation and a good prognosis. Recently, a few cases of complicated AM have been described. However, there are few reports with analysis of a relatively large cohort. To date, the largest analysis of AM was reported by Gilks et al. [6]. The extreme rarity of AM of the uterine cervix suggests that there is no accurate prognosis or standard treatment.
The major symptoms of AM are abnormal vaginal discharge and vaginal bleeding. The symptoms caused by secretion of the tumor itself are the most characteristic symptoms in patients with AM. A profuse vaginal discharge occurred in all cases reported by Hirai et al. [6] and 11 of 26 cases reported by Gilks et al. [7]. In the present study, 77.7% of patients had the major AM symptoms (profuse vaginal discharge in 8/18 and abnormal vaginal bleeding in 6/18). When there are grossly normal vaginal and cervical findings in patients with these major symptoms, the presence of a multi‐locular cystic mass in the uterine cervix as detected by ultrasonography can help in making a clinical diagnosis of AM (Fig. 1).
Figure 1.
Transvaginal ultrasonography axial scan showing a multilocular cystic mass in the deep cervical portion. The tumor was histologically confirmed to be adenoma malignum after a hysterectomy.
A preoperative histologic diagnosis of AM is often difficult if the physician does not examine patients with particular concern about this disease. The routine screening method for a diagnosis of uterine cervical cancer is a cytological evaluation [Papanicolaou (Pap) smear]. Because the lesion is located deep in the endocervix and AM is an extremely rare disease, it is difficult to determine an accurate cytological diagnosis. Hirai et al. reported that exfoliative cytology seems to be an important diagnostic technique for detecting this rare subtype of cervical adenocarcinoma [7]. However, several studies concluded that a Pap smear is not as important in detecting AM because of the minimal cytologic deviation [[1], [6], [8]]. This study revealed a negative Pap smear in 14 cases (77.7%) and two cases of adenocarcinoma on the Pap smear were found to be a co‐occurrence of an AM and an endocervical‐type adenocarcinoma of the uterine cervix. In the present study, eight patients had a cervical conization or D&C (one patient underwent both conization and D&C). All eight cases were diagnosed preoperatively with AM.
McGowan et al. reported that Peutz–Jeghers syndrome may sometimes be complicated by AM [9]. In the present series, there were two cases (11.1%) of Peutz–Jeghers syndrome for women aged 29 and 31 years. Both patients were treated for bowel problems before AM was detected. The overall incidence of carcinoma in these patients varies from 20% to 50%, and the cumulative risk of cervical cancer occurring between the ages of 15 and64 years is 10% [[10], [11]]. One case was advanced stage IV and the patient died of the disease after the initial diagnosis and surgical treatment with CCRT. The other case was FIGO stage IB2. This patient was given two courses of neoadjuvant chemotherapy, followed by a laparoscopic radical hysterectomy with PLND. Three courses of adjuvant chemotherapy were administered and no clinical evidence of recurrence was observed during a 26‐month follow‐up period. This case was previously reported [12].
The prognosis for AM is controversial. An early report suggested an unfavorable prognosis in patients with AM [4]. Silverberg and Hurt questioned this prognosis because four of five patients in their series were disease‐free for at least 3 years [5]. More recently, findings by Gilks et al. [6] for the largest case study were in agreement with those of McKelvey and Goodlin [4] and Kaku and Enjoji [13]. However, Hirai et al. reported that most neoplasms in these unfavorable reports were discovered at an advanced stage [7]. Moreover, AM tumors are often treated based on clinical understaging and undertreatment, which can result in a relatively poor prognosis. This study with a relatively large cohort of 18 AM cases suggests that the prognosis for these neoplasms is very good and might be consistent with that for other forms of well‐differentiated adenocarcinomas of the cervix. In this series, 16 of the 18 cases are well with no clinical evidence of recurrence after a mean follow‐up period of 49.2 months. The 5‐year survival rate was 88.8% (Table 3).
Table 3.
Survival outcomes.
| Adjuvant therapy | 8/18 (44.4%) |
| CCRT | |
| Weekly cisplatin | 2/8 (25.0%) |
| Paclitaxel and cisplatin | 2/8 (25.0%) |
| RT alone | 3/8 (37.5%) |
| Chemotherapy alone (paclitaxel/cisplatin) | 1/8 (12.5%) |
| Prognosis | |
| Recurrence | 0 |
| Progression | 2/18 (11.1%) |
| Death | 2/18 (11.1%) |
| Mean follow‐up (m) | 49.2 (range 4–168) |
CCRT = concurrent chemoradiation therapy.
The main treatment for AM is surgery. No standard surgical treatment has been established because of its rarity, preoperative misdiagnosis, and a scarcity of data on surgical outcomes according to hysterectomy type. In this series, five patients with a type I hysterectomy without PLND all had a preoperative misdiagnosis of benign disease. The eight patients with a type III hysterectomy were all diagnosed preoperatively with cervical malignant neoplasms and all cases received planned surgical treatment. One younger unmarried woman among the eight patients with a preoperative diagnosis of AM underwent a laparoscopic radical hysterectomy after receiving two neoadjuvant chemotherapy sessions to reduce the tumor size. The other five patients with a type I hysterectomy with PLND were all diagnosed intra‐operatively through a frozen biopsy. These data raise the following questions: (1) is a type III hysterectomy necessary for treating a pure AM of FIGO stage I?; and (2) as there are few data regarding the need for adjuvant therapy, which type of adjuvant therapy is the best treatment?
In conclusion, the prognosis for AM was found to be better than that of ordinary cervical adenocarcinoma. A routine cytological screening test has low power in detecting AM. Therefore, an additional deep biopsy (cone biopsy or endocervical curettage) is necessary to diagnose this rare tumor preoperatively when there is any clinical suspicion of AM, a patient has profuse vaginal discharge, and there is a multilobular cystic mass in the uterine cervix. Additional studies will be needed to diagnose AM correctly and determine definitive management principles through meta‐analysis using multicenter data.
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